Citations

Abstract Purpose: Oncolytic viruses are self-amplifying anticancer agents that make use of the natural ability of viruses to kill cells. Adenovirus serotype 5 (Ad5) has been extensively tested against solid cancers, but less so against B-cell cancers because these cells do not generally express the coxsackie and adenoviral receptor (CAR). To determine whether other adenoviruses might have better potency, we “mined” the adenovirus virome of 55 serotypes for viruses that could kill B-cell cancers. Experimental Design: Fifteen adenoviruses selected to represent Ad species B, C, D, E, and F were tested in vitro against cell lines and primary patient B-cell cancers for their ability to infect, replicate in, and kill these cells. Select viruses were also tested against B-cell cancer xenografts in immunodeficient mice. Results: Species D adenoviruses mediated most robust killing against a range of B-cell cancer cell lines, against primary patient marginal zone lymphoma cells, and against primary patient CD138+ myeloma cells in vitro. When injected into xenografts in vivo, single treatment with select species D viruses Ad26 and Ad45 delayed lymphoma growth. Conclusions: Relatively unstudied species D adenoviruses have a unique ability to infect and replicate in B-cell cancers as compared with other adenovirus species. These data suggest these viruses have unique biology in B cells and support translation of novel species D adenoviruses as oncolytics against B-cell cancers. Clin Cancer Res; 17(21); 6712–22. ©2011 AACR.

A newly identified gene fusion defines the vascular cancer epithelioid hemangioendothelioma and encodes a chimeric transcription factor.

AbstractLung cancer in lifetime never smokers is distinct from that in smokers, but the role of separate or overlapping carcinogenic pathways has not been explored. We therefore evaluated a comprehensive panel of 11,737 single-nucleotide polymorphisms (SNP) in inflammatory-pathway genes in a discovery phase (451 lung cancer cases, 508 controls from Texas). SNPs that were significant were evaluated in a second external population (303 cases, 311 controls from the Mayo Clinic). An intronic SNP in the ACVR1B gene, rs12809597, was replicated with significance and restricted to those reporting adult exposure to environmental tobacco smoke. Another promising candidate was an SNP in NR4A1, although the replication OR did not achieve statistical significance. ACVR1B belongs to the TGFR-β superfamily, contributing to resolution of inflammation and initiation of airway remodeling. An inflammatory microenvironment (second-hand smoking, asthma, or hay fever) is necessary for risk from these gene variants to be expressed. These findings require further replication, followed by targeted resequencing, and functional validation.Significance: Beyond passive smoking and family history of lung cancer, little is known about the etiology of lung cancer in lifetime never smokers that accounts for about 15% of all lung cancers in the United States. Our two-stage candidate pathway approach examined a targeted panel of inflammation genes and has identified novel structural variants that appear to contribute to risk in patients who report prior exposure to sidestream smoking. Cancer Discovery; 1(5): 420–9. ©2011 AACR.This article is highlighted in the In This Issue feature, p. 367

Diabetic ketoacidosis (DKA) during pregnancy carries significant risk of intrauterine fetal demise, but little is known about its postnatal sequelae in surviving neonates. We report here the case of an infant who was born to a mother with White's class C diabetes mellitus during an episode of DKA. Throughout pregnancy her glucose control was suboptimal, as evidenced by a predelivery glycosylated hemoglobin level of 8.1%. At 33 weeks' gestation, the mother presented with nausea and vomiting, a serum glucose concentration of 575 mg/dL, and other metabolic derangements consistent with DKA. Despite rehydration and insulin therapy, fetal distress necessitated cesarean delivery. At birth the infant required intubation, but her clinical status quickly improved and she was extubated within the first day of life. However, on day-of-life 4 she exhibited seizure-like activity, and subsequent brain MRI revealed bilateral basal ganglia infarctions. Previous research has revealed that the keto acid β-hydroxybutyrate (β-OHB) can cross the placenta into the fetal circulation and thereafter accumulate in the fetal brain, which leads to severe metabolic derangements. Furthermore, β-OHB accumulates rapidly in the basal ganglia of older children during episodes of DKA, wherein its presence is associated with neuronal injury. We suspect that transplacental transfer of maternal β-OHB led to an acquired ketoacidosis in the fetus and that accumulation of β-OHB contributed to neuronal injury and subsequent infarction of the basal ganglia. Further research is necessary to better characterize neonatal complications of maternal DKA, as well as the possible inclusion of β-OHB levels in the goal-directed treatment of this disease.